Inoperable malignant bowel obstruction: palliative interventions outcomes - mixed-methods systematic review.

BACKGROUND: Parenteral nutrition (PN) and palliative venting gastrostomies (PVG) are two interventions used clinically to manage inoperable malignant bowel obstruction (MBO); however, little is known about their role in clinical and quality-of-life outcomes to inform clinical decision making. AIM: To examine the impact of PN and PVG on clinical and quality-of-life outcomes in inoperable MBO. DESIGN: A mixed-methods systematic review and narrative synthesis. DATA SOURCES: The following databases were searched (from inception to 29 April 2021): MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL, Bielefeld Academic Search Engine, Health Technology Assessment and CareSearch for qualitative or quantitative studies of MBO, and PN or PVG. Titles, abstracts and papers were independently screened and quality appraised. RESULTS: A total of 47 studies representing 3538 participants were included. Current evidence cannot tell us whether these interventions improve MBO survival, but this was a firm belief by patients and clinicians informing their decision. Both interventions appear to allow patients valuable time at home. PVG provides relief from nausea and vomiting. Both interventions improve quality of life but not without significant burdens. Nutritional and performance status may be maintained or improved with PN. CONCLUSION: PN and PVG seem to allow valuable time at home. We found no conclusive evidence to show either intervention prolonged survival, due to the lack of randomised controlled trials that have to date not been performed due to concerns about equipoise. Well-designed studies regarding survival for both interventions are needed. PROSPERO REGISTRATION NUMBER: CRD42020164170.

Exploring pathways to optimise care in malignant bowel obstruction (EPOC): Protocol for a three-phase critical realist approach to theory-led intervention development for shared decision-making.

INTRODUCTION: Malignant bowel obstruction is a distressing complication of cancer, causing pain, nausea and vomiting, and often has a poor prognosis. Severe and rapidly developing symptoms, a lack of robust clinical guidelines and the need for multidisciplinary input make treatment decision-making challenging. Sharing decision-making with people with malignant bowel obstruction and their caregivers can be difficult, and inconsistent communication creates serious deficiencies in care by amplifying patients' distress and uncertainty. Little attention has been paid to the implicit influences on this process-for example, the role of discipline-related norms and the beliefs of decision-makers. This study will explore how these processes work and develop interventions to improve shared decision-making. METHODS AND ANALYSIS: Exploring Pathways to Optimise Care (EPOC) is a three-phase study set within a critical realist framework: (i) realist review, to develop explanatory theory describing collaborative decision-making in the management of malignant bowel obstruction; (ii) an in-depth interview study using modified grounded theory to explore the active ingredients of this collaboration in practice settings; and (iii) the presentation to stakeholders (practitioners, patients and caregivers) of integrated results from Phase I (theory developed from the literature) and Phase II (theory developed from current practice) as a basis for intervention mapping. We aim to produce recommendations to address the challenges, and to develop a set of tools to (i) aid interaction around shared decision-making and (ii) aid interprofessional interaction around the management of this condition. Registration details: The realist review is registered with PROSPERO (CRD42022308251).

Where are the inequalities in colorectal cancer care in a country with universal healthcare? A systematic review and narrative synthesis.

OBJECTIVE: Patients diagnosed with colorectal cancer living in more deprived areas experience worse survival than those in more affluent areas. Those living in more deprived areas face barriers to accessing timely, quality healthcare. These barriers may contribute to socioeconomic inequalities in survival. We evaluated the literature for any association between socioeconomic group, hospital delay and treatments received among patients with colorectal cancer in the UK, a country with universal healthcare. DESIGN: MEDLINE, EMBASE, CINAHL, CENTRAL, SCIE, AMED and PsycINFO were searched from inception to January 2023. Grey literature, including HMIC, BASE and Google Advanced Search, and forward and backward citation searches were conducted. Two reviewers independently reviewed titles, abstracts and full-text articles. Observational UK-based studies were included if they reported socioeconomic measures and an association with either hospital delay or treatments received. The QUIPS tool assessed bias risk, and a narrative synthesis was conducted. The review is reported to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020. RESULTS: 41 of the 7209 identified references were included. 12 studies evaluated 7 different hospital intervals. There was a significant association between area-level deprivation and a longer time from first presentation in primary care to diagnosis. 32 studies evaluated treatments received. There were socioeconomic inequalities in surgery and chemotherapy but not radiotherapy. CONCLUSION: Patients with colorectal cancer face inequalities across the cancer care continuum. Further research is needed to understand why and what evidence-based actions can reduce these inequalities in treatment. Qualitative research of patients and clinicians conducted across various settings would provide a rich understanding of the complex factors that drive these inequalities. Further research should also consider using a causal approach to future studies to considerably strengthen the interpretation. Clinicians can try and mitigate some potential causes of colorectal cancer inequalities, including signposting to financial advice and patient transport schemes. PROSPERO REGISTRATION NUMBER: CRD42022347652.

Where are the inequalities in ovarian cancer care in a country with universal healthcare? A systematic review and narrative synthesis.

INTRODUCTION: Patients diagnosed with ovarian cancer from more deprived areas may face barriers to accessing timely, quality healthcare. We evaluated the literature for any association between socioeconomic group, treatments received and hospital delay among patients diagnosed with ovarian cancer in the United Kingdom, a country with universal healthcare. METHODS: We searched MEDLINE, EMBASE, CINAHL, CENTRAL, SCIE, AMED, PsycINFO and HMIC from inception to January 2023. Forward and backward citation searches were conducted. Two reviewers independently reviewed titles, abstracts, and full-text articles. UK-based studies were included if they reported socioeconomic measures and an association with either treatments received or hospital delay. The inclusion of studies from one country ensured greater comparability. Risk of bias was assessed using the QUIPS tool, and a narrative synthesis was conducted. The review is reported to PRISMA 2020 and registered with PROSPERO [CRD42022332071]. RESULTS: Out of 2876 references screened, ten were included. Eight studies evaluated treatments received, and two evaluated hospital delays. We consistently observed socioeconomic inequalities in the likelihood of surgery (range of odds ratios 0.24-0.99) and chemotherapy (range of odds ratios 0.70-0.99) among patients from the most, compared with the least, deprived areas. There were no associations between socioeconomic groups and hospital delay. POLICY SUMMARY: Ovarian cancer treatments differed between socioeconomic groups despite the availability of universal healthcare. Further research is needed to understand why, though suggested reasons include patient choice, health literacy, and financial and employment factors. Qualitative research would provide a rich understanding of the complex factors that drive these inequalities.

Geriatric Oncology as an Unmet Workforce Training Need in the United Kingdom-A Narrative Review by the British Oncology Network for Undergraduate Societies (BONUS) and the International Society of Geriatric Oncology (SIOG) UK Country Group.

Cancer is a disease associated with ageing. Managing cancer in older adults may prove challenging owing to pre-existing frailty, comorbidity, and wider holistic needs, as well as the unclear benefits and harms of standard treatment options. With the ongoing advances in oncology and the increasing complexity of treating older adults with cancer, the geriatric oncology field must be a priority for healthcare systems in education, research, and clinical practice. However, geriatric oncology is currently not formally taught in undergraduate education or postgraduate training programmes in the United Kingdom (UK). In this commentary, we outline the landscape of geriatric oncology undergraduate education and postgraduate training for UK doctors. We highlight current challenges and opportunities and provide practical recommendations for better preparing the medical workforce to meet the needs of the growing population of older adults with cancer. This includes key outcomes to be considered for inclusion within undergraduate and postgraduate curricula.

Geriatric assessment prior to cancer treatment: A health economic evaluation.

INTRODUCTION: To address uncertainty regarding the cost-effectiveness of implementing geriatric assessment (GA) in oncology practice, we undertook a synthetic, model-based economic evaluation. MATERIALS AND METHODS: A decision-analytic model with embedded Markov chains was developed to simulate a cost-effectiveness analysis of implementing GA within standard oncological care compared to current practice. This was for patients aged 77 years (the mean age in included trials) receiving chemotherapy or surgery as first-line treatment. Assumptions were made about model parameters, based on available literature, to calculate the incremental net health benefit (INHB) of GA, using a data synthesis. RESULTS: GA has additional costs over standard care alone of between £390 and £576, depending upon implementation configuration. When major assumptions about the effectiveness of GA were modelled, INHB was marginally positive (0.09-0.12) at all cost-effectiveness thresholds (CETs). If no reduction in postoperative complications was assumed, the intervention was shown not to be cost-effective (INHB negative at all CETs). When used before chemotherapy, with minimal healthcare staffing inputs and technological assistance, GA is cost-effective (INHB positive between 0.06 and 0.07 at all CETs). DISCUSSION: Considering emerging evidence that GA improves outcomes in oncology, GA may not be a cost-effective intervention when used for all older adults with cancer. However, with judicious selection of implementation models, GA has the potential to be cost-effective. Due to significant heterogeneity and centre dependent success in implementation and effectiveness, GA is difficult to study in oncology settings. Stakeholders could take a pragmatic approach towards GA introduction with local evaluation favoured over generalisable research. Because GA tends towards utilitarianism and has no safety issues, it is a suitable intervention for more widespread implementation.

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial).

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.

Evaluating a web-based computer-tailored physical activity intervention for those living with and beyond lung cancer (ExerciseGuide UK): protocol for a single group feasibility and acceptability study.

BACKGROUND: Lung cancer is the leading cause of cancer-related death globally. Physical activity and exercise provide unequivocal benefits to those living with and beyond lung cancer. However, few of those living with and beyond cancer meet the national physical activity guidelines. Various barriers exist for this population's engagement in physical activity and exercise, such as the lack of knowledge and lack of tailored information, little access to exercise specialists, fatigue, and mobility challenges. Digitally delivered programmes have the potential to address several of these barriers, with techniques like "computer-tailoring" available to enable the delivery of tailored content at a time and place that is convenient. However, evaluation of such programmes is needed prior to implementation. This protocol describes a single group study that will examine the feasibility and acceptability of an online tool (ExerciseGuide UK) that provides those living with and beyond lung cancer web-based computer-tailored physical activity prescription and modules underpinned by behaviour change theories. METHODS: Thirty-five individuals diagnosed with lung cancer, or cancer affecting the lung (e.g. pleural mesothelioma), will be recruited into a single-intervention arm. The platform will provide tailored resources and a personalised physical activity programme using IF-THEN algorithms. Exercise prescription will be tailored on factors such as self-reported specific pain location, exercise history, and current physical fitness. In addition, modules grounded in behaviour change will supplement the physical activity programme and will focus on topics such as exercise benefits, safety, goal setting, and tracking. The primary outcome will be assessed using pre-established criteria on feasibility and mixed-methods approach for acceptability. Secondary outcomes will explore changes in the physical activity, quality of life, anxiety, and depression. DISCUSSION: This manuscript describes the protocol for a study examining the feasibility and acceptability of a web-based computer-tailored physical activity intervention for those living with and beyond lung cancer. The publication of this protocol aims to increase the transparency of the methods, report pre-determined criteria, and aid replication of the study and associated materials. If feasible and acceptable, this intervention will inform future studies of digital-based interventions. TRAIL REGISTRATION: ClinicalTrails.gov , NCT05121259. Registered on November 16, 2021.

Exploring hypoxic biology to improve radiotherapy outcomes.

Ionising radiotherapy is a well-established, effective cancer treatment modality, whose efficacy has improved with the application of newer technological modalities. However, patient outcomes are governed and potentially limited by aspects of tumour biology that are associated with radioresistance. Patients also still endure treatment-associated toxicities owed to the action of ionising radiation in normoxic tissue adjacent to the tumour mass. Tumour hypoxia is recognised as a key component of the tumour microenvironment and is well established as leading to therapy resistance and poor prognosis. In this review, we outline the current understanding of hypoxia-mediated radiotherapy resistance, before exploring targeting tumour hypoxia for radiotherapy sensitisation to improve treatment outcomes and increase the therapeutic window. This includes increasing oxygen availability in solid tumours, the use of hypoxia-activated prodrugs, targeting of hypoxia-regulated or associated signalling pathways, as well as the use of high-LET radiotherapy modalities. Ultimately, targeting hypoxic radiobiology combined with precise radiotherapy delivery modalities and modelling should be associated with improvement to patient outcomes.

CANcer BEhavioural nutrition and exercise feasibility trial (CanBenefit); phase I qualitative interview findings.

BACKGROUND: Older people with lung cancer are often frail and unfit due to their cancer and co-morbidities and may tolerate cancer treatments poorly. Physical activity (PA) and a healthy diet offer quality of life benefit to people with cancer before, during, and post treatment. However, older adults are poorly represented in the clinical trials on which recommendations were made. OBJECTIVE: To assess the acceptability, usefulness, and practicality of delivering a tailored wellbeing (PA and nutrition) intervention for older adults with lung cancer before, during, and after cancer treatments (chemotherapy and/or immunotherapy). METHODS: Semi-structured interviews conducted with nine patients with lung cancer and three patients with mesothelioma, ≥70 years and ten informal carers, and nine Multidisciplinary Team (MDT) members. A topic guide covered the acceptability, usefulness, and practicality of a wellbeing intervention as well as specific feedback on individual components. Data were subjected to thematic analysis. FINDINGS: Four themes were generated: current lack of wellbeing care in clinical work; preferred "can have" dietary and "can do" PA advice; peer support as facilitating factor; and barriers to compliance including patients' psychological and physical issues as well as current cancer pathway and staffing issues. CONCLUSION: Older adults with lung cancer would welcome a proactive, clear and instructive, wellbeing intervention. Many barriers to compliance exist, particularly before and during cancer treatments due to the psycho-social impact of diagnosis, and the effects of cancer treatment. The intervention must be tailored to individual need and address physical limitations, psychological and social welfare in addition to PA and nutritional advice.

Implementation of geriatric assessment in oncology settings: A systematic realist review.

Older adults with cancer are more likely to have worse clinical outcomes than their younger counterparts, and shared decision-making can be difficult, due to both complexity from adverse ageing and under-representation in clinical trials. Geriatric assessment (GA) has been increasingly recognised as a predictive and prehabilitative tool for older adults with cancer. However, GA has been notoriously difficult to implement in oncological settings due to workforce, economic, logistical, and practical barriers. We aimed to review the heterogenous literature on implementation of GA in oncology settings to understand the different implementation context configurations of GA and the mechanisms they trigger to enable successful implementation. A systematic realist review was undertaken in two stages: i) systematic searches with structured data extraction combined with iterative key stakeholder consultations to develop programme theories for implementing GA in oncology settings; ii) synthesis to refine programme theories. Medline, Embase, PsycInfo, Cochrane Library, CINAHL, Web of Science, Scopus, ASSIA, Epistemonikos, JBI Database of Systematic Reviews and Implementation Reports, DARE and Health Technology Assessment were searched. Four programme theories were developed from 53 included articles and 20 key stakeholder consultations addressing the major barriers of GA implementation in oncology practice: time (leveraging non-specialists), funding (creating favourable health economics), practicalities (establishing the use of GA in cancer care), and managing limited resources. We demonstrate that a whole system approach is required to improve the implementation of GA in cancer settings. This review will help inform policy decisions regarding implementation of GA and provide a basis for further implementation research.

The care of older cancer patients in the United Kingdom.

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient's biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one's fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer.

Physical activity and nutrition interventions for older adults with cancer: a systematic review.

PURPOSE: The aim of this review was to summarize the current literature for the effectiveness of activity and nutritional based interventions on health-related quality of life (HRQoL) in older adults living with and beyond cancer (LWBC). METHODS: We conducted systematic structured searches of CINAHL, Embase, Medline, Cochrane CENTRAL databases, and bibliographic review. Two independent researchers selected against inclusion criteria: (1) lifestyle nutrition and/or activity intervention for people with any cancer diagnosis, (2) measured HRQoL, (3) all participants over 60 years of age and (4) randomized controlled trials. RESULTS: Searches identified 5179 titles; 114 articles had full text review, with 14 studies (participant n = 1660) included. Three had nutrition and activity components, one, nutrition only and ten, activity only. Duration ranged from 7 days to 1 year. Interventions varied from intensive daily prehabilitation to home-based gardening interventions. Studies investigated various HRQoL outcomes including fatigue, general and cancer-specific quality of life (QoL), distress, depression, global side-effect burden and physical functioning. Eight studies reported significant intervention improvements in one or more QoL measure. Seven studies reported using a psychosocial/theoretical framework. There is a gap in tailored nutrition advice. CONCLUSIONS: Among the few studies that targeted older adults with cancer, most were activity-based programmes with half reporting improvements in QoL. Future research should focus on or include tailored nutrition components and consider appropriate behaviour change techniques to maximize potential QoL improvement. IMPLICATIONS FOR CANCER SURVIVORS: More research is needed to address the research gap regarding older adults as current recommendations are derived from younger populations.

The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma.

Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72 h treatment with the lipoxygenase pathway inhibitors baicalein, licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6 µM to 20.7 µM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable.

LungCARD - Report on worldwide research and clinical practices related to lung cancer.

PURPOSE: The management of advanced lung cancer has evolved tremendously over the past two decades. Increasing understanding of the molecular changes that drive tumor progression has transformed the treatment of this disease. Nevertheless, various countries differ in the degree of implementation of genetic tests and the availability of innovative drugs. The LungCARD consortium created a questionnaire to collect information about the local research and clinical practices related to lung cancer diagnosis and therapy. METHODS: A survey composed of 37 questions related to specific lung cancer pharmacogenomics and therapy, was distributed among 18 countries. RESULTS: All together 36 responses were gathered, answered mainly by clinicians. The majority attends 50-200 cancer cases per month, 20-50% of all cancer cases are lung cancer patients, and more than 80% are with non-small-cell lung cancer (NSCLC). Targeted therapy is applied to 50% on average of all NSCLC patients. Forty five percent of participating medical oncologists are treating their patients with immunotherapy. More than 90% of the respondents are guided by results of genetic tests in introducing targeted treatment. As expected, the majority orders EGFR gene testing (85%), followed by ALK (58%) and KRAS testing (32%). Almost all (96%) agreed that more biomarkers should be included in routine genetic testing (ROS1, anti-PDL1, KRAS, MET, HER2, BRAF...), and that blood test is useful in pharmacogenomic testing. CONCLUSION: There is a great variation between countries with respect to all discussed topics. However, the majority recognized a necessity of introducing next generation sequencing (NGS)-based diagnostics and potential of testing from blood. The biggest problem in the treatment of NSCLC is still an access to innovative drugs.

Variation in geographical treatment intensity affects survival of non-small cell lung cancer patients in England.

OBJECTIVES: We aimed to determine the geographical variation in the proportion of non-small cell lung cancer (NSCLC) patients undergoing curative treatment and assess the relationship between treatment access rates and survival outcomes. METHODS: We extracted cancer registration data on 144,357 lung cancer (excluding small cell tumours) patients diagnosed between 2009 and 2013. Surgical and radiotherapy treatment intensity quintiles were based on patients' Clinical Commissioning Group (CCG) of residence. We used logistic regression to assess the effect of travel time and case-mix on treatment use and Cox regression to analyse survival in relation to treatment intensity. RESULTS: There was wide variation in the use of curative treatment across CCGs, with the proportion undergoing surgery ranging from 8.9% to 20.2%, and 0.4% to 16.4% for radical radiotherapy. The odds of undergoing surgery decreased with socioeconomic deprivation (OR 0.91, 95% CI 0.85-0.97), whereas the opposite was observed for radiotherapy (OR 1.16, 95% CI 1.08-1.25). There was an overall effect of travel time to thoracic surgery centre on the odds of undergoing surgery (OR 0.81, 95% CI 0.76-0.87 for travel time >55 min vs ≤15 min) which was amplified by the effect of deprivation. No clear association was observed for radiotherapy. Higher mortality rates were observed for the lower resection and radiotherapy quintiles (HR 1.08, 95% CI 1.04-1.12 and HR 1.06, 95% CI 1.02-1.10 for lowest vs. highest resection and radiotherapy quintile). CONCLUSION: There was wide geographical variation in the use of curative treatment and a higher frequency of treatment was associated with better survival.

Selection of employee personal protective equipment based on aggressive behavior in pediatric neuropsychiatry.

PURPOSE: Hospitalized patients with a developmental or intellectual disability and a psychiatric disorder (dual-diagnosis) often pose a risk to themselves or others leading to high injury rates for their providers. Therefore, evidence-based strategies to reduce employee injuries resulting from interactions are necessary. METHODS: To reduce injuries resulting from interactions with dual-diagnosis patients, the Initial Behavioural Assessment (IBA) and Protective Equipment Decision Key (PEDK) were used in inpatient neuropsychiatry. The IBA-PEDK identify patients' aggressive behaviors to provide employees with personal protective equipment (PPE). Inter-rater reliability, validity, and adherence were examined. RESULTS: Injuries significantly decreased after implementing the IBA-PEDK. The average kappa coefficient was 0.64 with a 90.6% agreement. Ninety-three percent of respondents reported wearing PPE at the time of injury. CONCLUSIONS: A quick, user-friendly tool that provides a standardized method for determining PPE based on patient-specific behavior can significantly reduce aggression-related injuries.

MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity.

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.

IMPORTANCE: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. OBJECTIVE: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. INTERVENTIONS: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. RESULTS: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01279967.